3-(5-nitro-2-furyl)-delta2-1, 2, 4-triazolines



United States Patent 3,391,155 S-(S-NITRO-Z-FURYD-N-1,2,4-TRIAZOLINESLouis Edmond Benjamin, Norwich, N.Y., assignor to The Norwich PharmacalCompany, Norwich, N.Y., a corporation of New York No Drawing.Continuation-impart of application Ser. No. 247,514, Dec. 27, 1962. Thisapplication July 11, 1963, Ser. No. 294,240

7 Claims. (Cl. 26(i-308) ABSTRACT OF THE DISCLOSURE A new series of3-(5-nitro-2-furyl)A -1,2,4,-triazolines possess chemotherapeuticactivity against various bacteria and coccidia.

This application is a continuationdn part of my copending applicationSer. No. 247,514, filed Dec. 27, 1962.

This invention relates to novel chemical compounds which may berepresented by the formula:

Also comprehended within this invention are methods for preparing thesecompounds and compositions containing them.

These compounds are crystalline solids, somewhat soluble in water andmore soluble in organic solvents. They are highly active parasiticides,being particularly noteworthy for their toxic action upon bacteria andcoccidia. In sub-toxic doses they combat lethal infections induced byStaphylococcus aureus and Salmonella typhosa. For instance, whenadministered perorally to mice lethally infected by the aforementionedbacteria in low doses ranging from 26-102 n1g./kg. they controlmortality. When administered via the feed supply, at levels of from(LOU-0.022%, to chickens exposed to and infected by Eimeria tenella,they combat the mortality and morbidity provoked by that protozoan whenleft unchecked.

These compounds are adapted to be readily combined as the activeconstituent of compositions designed for facile administration to combatinfectious processes. They may be formulated in the form of tablets,suspensions, elixirs, solutions, troches and the like using exc-ipientsand adjuvants commonly employed in the apothecary art. In veterinaryuse, the feed and water supply of animals serve as additional convenientcarriers for their administration.

These compounds are readily prepared. In their preparation it ispreferred to initially react an alkyl 5- nitro-2-furimidate salt, suchas the hydrochloride, with a carbonyl derivatizing agent; e.g.,semicarbazide, aminoguanidine or substituted derivatives thereof, in thepresence of a solvent such as alcohol and at ambient or slightlyelevated temperature to hasten the reaction; followed by thermallyeffecting ring closure of the resultant product in the presence of ahigh boiling solvent such as nitrobenzene. The products are recovered inconventional fashion; e.g. by filtration from the cooled reactionmixture or solvent precipitation with immiscible solvents, such asdiethyl ether, followed by filtration. They may be recrystallized ,fromcommon solvents such as water, glacial 3,361,155 Fatented July 2, 1968ICE acetic acid, dimethylformamide, methanol and mixtures thereof.

The 3 a (5 nitro-2-furyl)-A -1,2,4-triazolines thus obtained are readilyconverted into the further triazoline derivatives of this invention bytreatment with reagents such as acetyl chloride, acetic anhy'dride,acetic acid, ethylene bromohydrin, methyl iodide, and 0,0-diethylphosphorochloridothioate.

In order that this invention may be readily available to and understoodby those skilled in the art, the following illustrative, but notlimitative, examples thereof are supplied:

Example I.5-oxo-3-(5-nitro-2-furyl)--A -l,2,4triazoline (A) Ethyl5-nitro-2-fu1imidate hydrochloride. A suspension of 900 grams (6.5moles) of 5-nitro-2- furonitrile in 5450 ml. of ethanol (anhydrous) in a12 liter flask, equipped with a stirrer and gas-inlet tube is cooled to10 C. with an ice-water bath. Dry HCl gas is added rapidly withcontinued cooling for about 1.5 hours until a nearly complete solutionis obtained. At this point the product begins to precipitate from thesolution and the flow of HCl gas in continued at a reduced rate for twoto three hours. The nearly white product is separated by filtration andis washed with 1500 ml. of ice-cold ethanol and rinsed with anhydrousether. After drying overnight at 60 C. the product is pale yellow,weighing 808 g. (56% of theory), M.P. 158-160" C.

(B) Preparation of N-ureido-S-nitro 2 furamid-ine. A mixture of ethylS-nitro-Z-furimidate hydrochloride (100 g.; 0.45 mole), semicarbazide(34 g.; 0.4-5 mole), and ethanol (800 ml.) is heated at 50-55 C. for 30minutes with occasional stirring. The mixture is cooled and diluted withwater (2.1). An orange solid separates which is collected by filtration.The yield of product is 60 g. (63%); MP. 274-275 C.

Anaylsis.Calcd. for C H N O C, 33.81; H, 3.31; N, 32.86. Found: C,34.07; H, 3.48; N, 32.81.

(C) Preparation of 5-oxo-3-(5-nitro-2-furyl)-A -1,2,4- triazoline.-Asolution of 5-11itro-N-ureido-2-furarnidine (60 g.; 0.28 mole) innitrobenzene (450 m1.) is boiled in a l 1. flash for 15 minutes. Themixture is cooled and diluted with ether (400 ml) The dark solid whichseparates is collected by filtration and is washed with ether. Theproduct weighs 43 g. (78%) and melts at about 270 C. Recrystallizationof the product from 4 l. of water gives a pale yellow solid (31 g.);M.P. 277- 279 C.

A-naIysis.-Calcd. for C H N O C, 36.74; H, 2.06; N, 28.57. Found: C,36.75; H, 2.31; N, 28.64.

Example II.-5-irnino-3-(5-nitro-2-furyl)-A -1,2,4- triazoline (A) Nguanidino 5-nitro-2-furarnidine dihydrochloride.-Aminoguanidinehydrochloride (55.5 g.; 0.5 mole) is dissolved in dimethylforrnamide(600 m1.) at 60 C. To this solution is added ethyl S-nitrO-Z'furimidatehydrochloride (110 g.; 0.5 mole). The solution is heated at 50- 60 C.for 30 minutes. The solution is cooled and diluted with ether until anoil separates. After decanting the ethereal layer, the oily residue istriturated with ether and then suspended in ethanol. The crystals arecollected by filtration, washed with ether, and dried at 80 C. The yieldof product is g. (63%); M.P. 204-206 C.

Analysis.--Calcd. for C HgN503'2HC1: C, 25.26; H, 3.54; N, 29.48; Cl,24.87. Found: C, 25.23; H, 3.58; N, 29.49; Cl, 25.14.

(B) Preparation of 5-imino-3(5-nitro-2-furyl)-A -1,2, 4-triazoline.-Asolution of N-guanidino-5-nitro-2-furamidine dihydrochloride (90 g.) innit'robenzene (400 ml.) is refluxed for 10-15 minutes. The hotnitrobenzene solution is decanted from the solid residue. A yellow solidseparates from the nitrobenzene solution on cooling. The coolnitrobenzene solution is diluted with ether and is filtered. The yellowsolid is washed with ether and is dried by suction. The yield of productis 32 g. (51%); M.P. 277-279 C. This may be recrystallized from water togive a melting point of 289-90 C.

Analysis.Calcd. for C H N O C, 36.93; H, 2.58; N, 25.89. Found: C,37.07; H, 2.80; N, 25.94.

Example III.-1 -methyl-5 -oxo-3- 5 -nitro-2-furyl A 1,2,4-triazoline (A)Preparation of 5-nitro-N-(l-methylureido)-2furamidine hydrochloride.-Amixture of ethyl 5-nitro-2- furimidate hydrochloride (110 g.; 0.5 mole),ethanol (500 ml.) and 2-methylsemicarbazide (45 g.; 0.5 mole) is heatedat 50-60 C. for 1 hour. The mixture is cooled and diluted with ether togive a light yellow solid which is slightly hygroscopic and is solublein water. The yield is approximately 100 g. (76%). This is converted tothe base by treatment with sodium carbonate. M.P. 185- 186 C.

Analysis.Calcd. for C H N O C, 37.01; H, 3.99; N, 30.83. Found: C,36.89; H, 3.77; N, 30.90.

(B) Preparation of l-methyl-5-oxo-3-(5-nitro-2-furyl)- A-1,2,4-triazoline.5-nitro-N (1 methylureido)-2-furamidine hydrochloride(100 g.) is heated in refluxing nitrobenzene (400 ml.) for minutes. Themixture is cooled and diluted with ether to give a dark solid. The solidis collected by filtration, washed with ether and dried by suction. Thecrude product weighs 60 g. (75%) and melts at 270 C. Recrystallizationfrom water (150 ml./ g.) gives the product as fluffy light yellowcrystals (35 g.); M.P. 275-276 C.

Analysis.-Calcd. for C H N O C, 40.00; H, 2.88; N, 26.66. Found: C,39.97; H, 2.70; N, 26.38.

Example 1V.1-acetyl-5-imino-3-(5-nitro-2-furyl)- A -1,2,4-triazoline Amixture of 5-imino-3-(5-nitro-2-furyl)-A -1,2,4-triazoline g.; 0.15mole), acetic anhydride (10 ml.), and glacial acetic acid (300 ml.) isheated on the steam bath for 20 minutes. A solution is obtainedinitially and a solid begins to separate from solution after a fewminutes of heating. The mixture is cooled, diluted with ether andfiltered. The yield of product is 34 g. (96%). The product is dissolvedin hot dirnethylformamide ml./ g.) treated with charcoal, and filtered.Hot water is added to the warm solution until it is slightly turbid. Thesolution is allowed to cool slowly. The yield is g.

Analysis.Calcd. for C H N O C, 40.51; H, 2.87; N, 29.53. Found: C,40.47; H, 2.86; N, 29.40.

Example V.5-acetylimino-3-( 5 -nitro-2-furyl) A 1 ,2,4-triazoline MethodA.-5-imino 3 (5-nitro-2-furyl)-A -l,2,4-triazoline (29 g.; 0.15 mole) isplaced in glacial acetic acid (580 ml.) and treated with dry hydrogenchloride (5.5 g.; 0.15 mole). The solution is refluxed for 20 hours. Thesolution is cooled, diluted with water and filtered. The solid weighs 25g. (70%) M.P. 340 C.

Recrystallization from dimethylformamide (15 ml./ g.) raises the meltingpoint to 343-345 C.

Method B.1-acetyl-5-imino 3 (5-nitro-2-furyl)-A 1,2,4-triazoline (4.8g.; 0.02 mole) is added with stirring to benzophenone (20 g.) at 290 C.When the addition is complete, the temperature is kept at 290-295 C. for2 minutes. After cooling to room temperature, the mixture is dilutedwith ether and filtered. Recrystallization from dimethylformamide (15ml./ g.) and water gives the product melting at 343345 C.

Analysis.Calcd. for C H N O C, 40.51; H, 2.97; N, 29.53. Found: C,40.76; H, 3.13; N, 29.41.

4 Example VI.1-(2-hydroxyethyl)-5-oxo-3-(5-nitro- 2-furyl) -A-1,2,4-triazoline (A) N-[l-(2hydroxyethyl)ureido]-5-nitro-2-furamidine.A mixture of ethyl5-nitro-2-furimidate hydrochloride (24 g.; 0.2 mole), 2-(2-hydroxyethyl)semicarbazide (24 g.; 0.2 mole), and ethanol (300 ml.) is heated at 5060C. for 30 minutes. After cooling, the mixture is diluted with ether toyield a gummy solid. The solid is dissolved in a minimal amount of waterand any undissolved solid filtered off. The filtrate is made basic withsodium carbonate and cooled. An orange solid separates and is collectedby filtration. The yield of product is 20 g. (40%) M.P. l75180 C. Thismay be converted to its hydrochloride with dry HCl gas in a suitablesolvent.

Analysis.Calcd. for: C H N O C, 37.35; H, 4.31; N, 27.23. Found: C,37.32; H, 4.13; N, 26.98.

(B) Preparation of 1-(2 hydroxyethyl)-5-oxo-3-(5 nitrO-Z-furyl)-A-1,2,4-triazoline.-A mixture of N-[l- (2-hydroxyethyl)ureido] 5nitrO-Z-furamidine hydrochloride and nitrobenzene (400 ml.) is heated atreflux for 15 minutes. The hot nitrobenzene solution is decanted fromthe dark solid which separates from solution. When the nitrobenzenesolution is cooled and diluted with ether, the product separates as abrown solid. Washing of the solid with 50% acetic acid gives agreenish-yellow solid (45 g., 38%); M.P. 230235 C. Recrystallization ofthe product from glacial acetic acid raises the melting point to 263264C.

Analysis.Calcd. for C H N O C, 40.00; H, 3.36; N, 23.33. Found: C,40.01; H, 3.39; N, 23.54.

Example VII.-0.0-diethyl- 1- [5-imino-3-(5-nitro-2- furyl) -A-l,2,4-triazoline] thiophosphate A mixture of5-imino-3-(5-nitro-2-furyl)-A -1,2,4-tri azoline (58.5 g.; 0.3 mole),0,0-diethyl phosphorochloridothioate (56.7 g.; 0.3 mole), sodiummethoxide (16.2 g.; 0.3 mole), and ethanol (1200 ml.) is refluxed for 30minutes. The hot solution is filtered by suction to remove sodiumchloride and any unreacted material. As the filtrate cools, the productseparates rapidly as a tan solid. Water is added to the filtrate tocomplete crystallization. The yield of product is 40 g. (38%); M.P. 158C. Recrystallization from methanol (30 ml./g.), gives 29 g. of paleyellow needles melting at 160-161 C.

Analysis.Calcd. for C H N O PS: C, 34.58; H, 4.07; N, 20.17; S, 9.23.Found: C, 34.57; H, 3.97; N, 20.08; S, 9.35.

Example VIII.1-methyl-5-imino-3 5 -nitro-2-furyl A -1,2,4-triazolineMETHOD A 1) Preparation of N-(l-methylguanidino)-5-nitro-2- furamidinedihydrochloride.A solution of l-amino-lmethylguanidine hydrochloride(37.2 g.; 0.3 mole), ethyl 5-nitro-2-furimidate hydrochloride (66.3 g.;0.3 mole), and dimethylformamide (300 m1.) is heated at 50-60 for 30minutes. The solution is cooled and diluted with ether. A gum separates.The gum is washed with ether and is heated on the steam bath to removetraces of ether. This product is used in the next step without furtherpurification.

(2) Preparation of 1-methyl-5-imino-3-(5-11itro-2-furyl)-A-l,2,4-triazoline.The N-(l-methylguanidino) 5- nitro-2'furamidinedihydrochloride is covered with nitrobenzene (200 ml.). The mixture isboiled for 10 minutes. The hot solution is decanted from the dark solidwhich separates. After cooling, the solution is diluted with ether. Asolid separates. The solid is collected by filtration, washed withether, and dried at C. A yield of 6 g. (10%) of product melting at 270C. is obtained. Recrystallization of the product from acetic acid (20:ml./ g.) gives a melting point of 306307 C.

Analysis.Calcd. for C H N O C, 40.19; H, 3.37; N, 33.48. Found: C,40.39; H, 3.47; N, 33.37.

METHOD B A mixture of -imino-3-(5-nitro-2-furyl)-L\ -1,2,4-triazoline(58.5 g.; 0.3 mole), methyl iodide (42.3 g.; 0.3 mole), and methanol(700 ml.) is heated to reflux. A solution of sodium methoxide (16.2 g.;0.3 mole) in methanol (200 ml.) is added dropwise to the stirredmixture. The mixture is refluxed for 1 hour after the addition iscompleted. The mixture is cooled and filtered, The product is obtainedas a brownish-yellow solid (40 g., 63%) melting at 300 C. The product isrecrystallized from glacial acetic acid ml./ g.) to give g. melting at302-3-03 C. Further recrystallization raises the melting point to306-307 C.; identical with l-methyl-S-imino- 3-(5-ni-tro-2-furyl)-A-1,2,4-triazoline, of Method A.

Example IX.5-imino- 1- (Z-hydroxyethyl -3- (5-nitro-2-furyl)-A-1,2,4-triazo1ine A mixture of the compound of Example II g., 0.33mole), ethylene bromohydrin (42 g., 0.33 mole), and ethanol (400 ml.) isplaced in a 1 1., three neck flask fitted with a stirrer, refluxcondenser, and dropping funnel. The stirred, refluxing mixture istreated with a solution of sodium methylate (18 g., 0.33 mole) inethanol (200 ml.). Reflux is continued for 1 hour after the addition iscompleted. The filtrate is evaporated almost to dryness at reducedpressure. Water (200 ml.) is added to the residue and the flask iscooled in an ice bath. The brown solid which separates is collected 'byfiltration and dried at to yield 17 g. of product (21.5%); M.P. ca. 200.Recrystallization of the product from nitromethane (30 ml./g.) raisesthe melting point to 213- 214.

Armlysis.-Calcd. for C l-1 14 0 C, 40.17; H, 3.79; N, 29.28. Found: C,40.24; H, 3.69; N, 29.34.

What is claimed is:

1. A compound of the formula:

wherein R is a member of the group consisting of hydrogen, methyl,acetyl, hydroxyethyl and diethoxythiophosphoryl; and R is a member ofthe group consisting of oxygen, irnino and acetylirnino.

2 1 methyl 5-imino-3-(5-nitro-2-furyl)-A -1,2,4-triazoline.

3. l-(2-hydroxyethyl)-5-oxo-3-(5 nitro-2-furyl)-A -1,2, 4-triazoline.

4. 5-imin0-3-(5-nitro-2-furyl-A -1,2,4-triazoline.

5. 1 acetyl-5-imino-3-(5-nitro-2-furyl)-A -1,2,4-triazoline.

6. l methyl 5-oxo-3-(5-nitro-2-furyl)-A -1,2,4-triazoline.

wherein R is selected from the group consisting of hy drogen and acetyl.

References Cited UNITED STATES PATENTS 2,385,284 9/1945 Knapp l67332,863,803 12/1958 Beng hiat et al. l6733 2,987,520 6/1961 Sickman 2603083,021,336 2/1962 Morin et a1 260-308 OTHER REFERENCES Weidinger et al.:(German Auslegeschrift) 1,073,499, Ian. 21, 1960.

Mndhoyan et al.: Chem. Abstracts, vol. 52, pages 12851-2 (1958).

Howard et al.: J. Org. Chem, vol. 26, pages 1651-2 (1961).

ALTON D. ROLLINS, Primary Examiner.

N. S. RIZZO, Examiner.

